Hydroxycarbonylphenyl substituted 4-(aminomethyl)-piperidine benzamides as 5HT4 antagonists

ABSTRACT

The present invention is concerned with novel compounds of formula (I) having 5HT 4 -antagonistic properties. The invention further relates to methods for preparing such novel compounds, pharmaceutical compositions comprising said novel compounds as well as the use as a medicine of said compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of Application No.PCT/EP2004/006274, filed Jun. 10, 2004, which application claimspriority from Appl. No. PCT/EP03/50239, filed Jun. 19, 2003.

The present invention is concerned with novel compounds of formula (I)having 5HT₄-antagonistic properties. The invention further relates tomethods for preparing such novel compounds, pharmaceutical compositionscomprising said novel compounds as well as the use as a medicine of saidcompounds.

WO-00/37461 discloses bicyclic benzamides of 3- or 4-substituted4-(aminomethyl)-piperidine derivatives having 5HT₄-antagonisticproperties.

The compounds of the present invention differ structurally from thecited art-known compounds by the presence of a different L radicalmoiety.

Unexpectedly, the present compounds of formula (I) have improvedmetabolic stability properties compared with the compounds disclosed inWO-00/37461.

The present invention concerns compounds of formula (I)

a stereochemically isomeric form thereof, an N-oxide form thereof, or apharmaceutically acceptable acid or base addition salt thereof,wherein

-   —R¹—R²— is a bivalent radical of formula    —O—CH₂—O—  (a-1),    —O—CH₂—CH₂—  (a-2),    —O—CH₂—CH₂—O—  (a-3),    —O—CH₂—CH₂—CH₂—  (a4),    —O—CH₂—CH₂—CH₂—O—  (a-5),    —O—CH₂—CH₂—CH₂—CH₂—  (a-6),    —O—CH₂—CH₂—CH₂—CH₂—O—  (a-7),    —O—CH₂—CH₂—CH₂—CH₂—CH₂—  (a-8),    wherein in said bivalent radicals optionally one or two hydrogen    atoms on the same or a different carbon atom may be replaced by    C₁₋₆alkyl or hydroxy,-   R³ is hydrogen, halo, C₁₋₆alkyl or C₁₋₆alkyloxy;-   R⁴ is hydrogen, halo, C₁₋₆alkyl; C₁₋₆alkyl substituted with cyano,    or C₁₋₆alkyloxy; C₁₋₆alkyloxy; cyano; amino or mono or    di(C₁₋₆alkyl)amino;-   R⁵ is hydrogen or C₁₋₆alkyl, and the —OR⁵ radical is situated at the    3- or 4-position of the piperidine moiety;-   L is a radical of formula    -Alk-R⁶  (1),    -Alk-X—R⁷  (b-2),    -Alk-Y—C(═O)—R⁹  (b-3),    -   wherein each Alk is C₁₋₁₂alkanediyl; and-   R⁶ is aryl;-   R⁷ is aryl;-   X is O, S, SO₂ or NR⁸; said R⁸ being hydrogen or C₁₋₆alkyl;-   R⁹ is aryl;-   Y is a direct bond, O, S, or NR¹⁰ wherein R¹⁰ is hydrogen or    C₁₋₆alkyl; and-   aryl represents phenyl substituted with 1, 2 or 3 substituents each    independently selected from hydroxycarbonyl.

As used in the foregoing definitions halo is generic to fluoro, chloro,bromo and iodo; C₁₋₄alkyl defines straight and branched chain saturatedhydrocarbon radicals having from 1 to 4 carbon atoms such as, forexample, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl andthe like; C₁₋₆alkyl is meant to include C₁₋₄alkyl and the higherhomologues thereof having 5 or 6 carbon atoms, such as, for example,2-methylbutyl, pentyl, hexyl and the like; C₁₋₁₂alkanediyl definesbivalent straight or branched chain hydrocarbon radicals containing from1 to 12 carbon atoms such as, for example, methanediyl, 1,2-ethanediyl,1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl,1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl,1,11-undecanediyl, 1,12-dodecanediyl and the branched isomers thereof.C₁₋₄alkanediyl defines bivalent straight or branched chain hydrocarbonradicals containing from 1 to 4 carbon atoms such as, for example,methanediyl, 1,2-ethanediyl, 1,3-propanediyl, and 1,4-butanediyl.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R— or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Compounds encompassing doublebonds can have an E or Z-stereochemistry at said double bond.Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) are able to form. The pharmaceutically acceptable acidaddition salts can conveniently be obtained by treating the base formwith such appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

The N-oxide forms of the compounds of formula (I), which may be preparedin art-known manners, are meant to comprise those compounds of formula(I) wherein one or several nitrogen atoms are oxidized to the N-oxide.Particularly those N-oxides are envisaged wherein thepiperidine-nitrogen is N-oxidized.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   a) —R¹—R²— is a radical of formula (a-5); and/or-   b) R³ is hydrogen, halo, methyl, or methoxy; and/or-   c) R⁴ is hydrogen, halo, or methyl; and/or-   d) R⁴ is fluoro; and/or-   e) aryl represents phenyl substituted with hydroxycarbonyl; and/or-   f) R⁵ is hydrogen or methyl, and the —OR⁵ radical is situated at the    3- or 4-position of the piperidine ring; and/or-   g) R⁵ is hydrogen or methyl, and the —OR⁵ radical is situated at the    3-position of the piperidine ring; and/or-   h) the —OR⁵ radical, wherein R⁵ is hydrogen or methyl, is situated    at the 3-position of the piperidine ring and is in the trans    position in relation to the methylene on the 4-position of the    piperidine moiety; and/or-   i) the —OR⁵ radical, wherein R⁵ is hydrogen or methyl, is situated    at the 3-position of the piperidine ring and is in the trans    position in relation to the methylene on the 4-position of the    piperidine moiety and the absolute configuration of said piperidine    moiety is (3S, 4S); and/or-   j) L is a radical of formula (b-2) wherein Alk is C₁₋₄alkanediyl, X    represents O , and and R⁷ is aryl wherein aryl is phenyl substituted    with hydroxycarbonyl.

Other interesting compounds are those compounds of formula (I) wherein

-   —R¹—R²— is a bivalent radical of formula    —O—CH₂—CH₂—CH₂—O—  (a-5),-   R³ is hydrogen, halo, C₁₋₆alkyl or C₁₋₆alkyloxy;-   R⁴ is hydrogen, halo, or C₁₋₆alkyl;-   R⁵ is hydrogen or C₁₋₆alkyl, and the —OR⁵ radical is situated at the    3- or 4-position of the piperidine moiety;-   L is a radical of formula    -Alk-X—R⁷  (b-2),    -   wherein each Alk is C₁₋₁₂alkanediyl; and-   R⁷ is aryl;-   X is O;-   aryl represents phenyl substituted with hydroxycarbonyl.

Particular compounds are those compounds of formula (I) wherein the —OR⁵radical, preferably representing hydroxy or methoxy, is situated at the3-position of the piperidine moiety having the trans configuration, i.e.the —OR⁵ radical is in the trans position in relation to the methyleneon the piperidine moiety.

More particular compounds are those compounds of formula (I) wherein thebivalent radical —R¹—R²— is a radical of formula (a-5), the —OR⁵ radicalrepresents hydroxy and is situated at the 3-position of the piperidinemoiety having the (3S-trans) configuration which corresponds to absolute(3S, 4S) configuration of said piperidine moiety.

Preferred compounds are those more particular compounds wherein L is aradical of formula (b-2) wherein Alk is C₁₋₄alkanediyl, and R⁷ is arylwherein aryl is phenyl substituted with hydroxycarbonyl.

More preferred compounds are those preferred compounds wherein Alk is1,3-propanediyl or 1,4-butanediyl and R⁷ is aryl wherein aryl is phenylsubstituted with hydroxycarbonyl situated at the 3- or 4-position of thephenyl moiety.

Most preferred compounds are those more preferred compounds wherein Alkis 1,3-propanediyl.

The compounds of formula (I) can be prepared by reacting an intermediateof formula (II) with an carboxylic acid derivative of formula (III) or,optionally a reactive functional derivative thereof, such as, e.g.carbonyl imidazole derivatives, acyl halides or mixed anhydrides. Saidamide-bond formation may be performed by stirring the reactants in anappropriate solvent, optionally in the presence of a base, such astriethylamine. The hydroxycarbonyl group present in substituents R⁶, R⁷and R⁹ is usually protected in the above described reaction sequence inthe form of an ester which is removed after the amide-bond formationreaction by hydrolysis under basic conditions.

The hydroxycarbonyl group present in substituents R⁶, R⁷ and R⁹ isusually protected in the above described reaction sequence in the formof an ester which is removed after the amide-bond formation reaction byhydrolysis under basic conditions.

Also compounds of formula (I) can generally be prepared by N-alkylatingan intermediate of formula (V) with an intermediate of formula (IV),wherein W is an appropriate leaving group such as, for example, halo,e.g. fluoro, chloro, bromo, iodo, or in some instances W may also be asulfonyloxy group, e.g. methanesulfonyloxy, benzenesulfonyloxy,trifluoromethanesulfonyloxy and the like reactive leaving groups. Thereaction can be performed in a reaction-inert solvent such as, forexample, acetonitrile, 2-pentanol, isobutanol, dimethyl acetamide orDMP, and optionally in the presence of a suitable base such as, forexample, sodium carbonate, potassium carbonate, N-methylpyrrolidone ortriethylamine. Stirring may enhance the rate of the reaction. Thereaction may conveniently be carried out at a temperature rangingbetween room temperature and the reflux temperature of the reactionmixture.

The hydroxycarbonyl group present in substituents R⁶, R⁷ and R⁹ isusually protected in the above described reaction sequence in the formof an ester which is removed after the amide-bond formation reaction byhydrolysis under basic conditions.

Intermediates of formula (V) can be prepared by reacting an intermediateof formula (VDI), wherein PG represents an appropriate art-knownprotective group, such as for example a tert-butoxycarbonyl or a benzylgroup or a photoremovable group, with an acid of formula (E), or anappropriate reactive functional derivative thereof, such as for examplecarbonyl imidazole derivatives, and subsequent deprotection of the thusformed intermediate, i.e. removal of PG by art-known methods.

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The starting materials and some of the intermediates are known compoundsand are commercially available or may be prepared according toconventional reaction procedures generally known in the art. Forexample, intermediates of formula (II) of (VI) can be prepared accordingto the methodologies described in WO-99/02156 or WO-00/37461.

Intermediates of formula (VI) can be prepared according to the generalmethodology described in WO-99/02156 or WO-00/37461 for the thereindescribed intermediates of formula (VIII).

The compounds of formula (I) as prepared in the hereinabove describedprocesses may be synthesized in the form of racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. The racemic compounds of formula (I) may beconverted into the corresponding diastereomeric salt forms by reactionwith a suitable chiral acid. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali.An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography using a chiralstationary phase. Said pure stereochemically isomeric forms may also bederived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I), the N-oxide forms, the pharmaceuticallyacceptable acid or base addition salts and stereoisomeric forms thereofpossess 5HT₄-antagonistic properties as described in Example C.1.

Furthermore the compounds of formula (I) have shown improved metabolicstability as described in Example C.2. These advantegous metabolicstability properties result in a reduced risk of drug-drug interactionon the level of cytochrome P450 enzymes such as e.g. CYP1A2, CYP3A4,CYP2D6, CYP2C9 and CYP2C19 and therefore the present compounds have animproved drug safety profile. Furthermore these advantageous metabolicstability properties may allow for a once daily administration of thecompounds of formula (I) instead of the usual administration of theactive ingredient on a regimen of between two or four intakes per daythereby giving more patient compliance.

In view of the 5HT₄-antagonistic properties of the compounds of thepresent invention, the subject compounds may generally be used in thetreatment or prophylaxis of gastrointestinal conditions such ashypermotility, irritable bowel syndrome (IBS), constipation- ordiarrhea-predominant IBS, pain- and non-pain-predominant IBS, bowelhypersensitivity, and the reduction of pain associated withgastrointestinal hypersensitivity and/or hyperactivity.

It is also believed that the compounds of formula (I) are useful in theprevention or prophylaxis of a disturbed, hampered or impaired gastricaccommodation such as dyspepsia. Dyspeptic symptoms are for exampleepigastric pressure, a lack of appetite, feeling of fullness, earlysatiety, nausea, vomiting, bloating and gaseous eructation.

The compounds of formula (I) may also be of use in the treatment ofother 5HT₄-related disorders such as boulimia and hyperphagia.

In view of the utility of the compounds of formula (I), it follows thatthe present invention also provides a method of treating warm-bloodedanimals, including humans, (generally called herein patients) sufferingfrom gastrointestinal conditions such as irritable bowel syndrome (IBS).Consequently a method of treatment is provided for relieving patientssuffering from conditions such as hypermotility, irritable bowelsyndrome (IBS), constipation- or diarrhea-predominant IBS, pain- andnon-pain-predominant IBS, bowel hypersensitivity, and the reduction ofpain associated with gastrointestinal hypersensitivity and/orhyperactivity.

The compounds of formula (I) may also be of potential use in othergastrointestinal disorders, such as those associated with upper gutmotility. In particular, they are of potential use in the treatment ofgastric symptoms of gastro-oesophageal reflux disease, such as heartburn(including episodic heartburn, nocturnal heartburn, and meal-inducedheartburn).

Furthermore, the 5HT₄-antagonistic compounds of formula (I) may also beof potential use in the treatment or prophylaxis of bladderhypersensitivity, overactive bladder, lower urinary tract symptoms,benign prostatic hypertrophy (BPH), prostatis, detrusor hyperreflexia,outlet obstruction, urinary frequency, nocturia, urinary urgency, pelvichypersensitivity, urge incontinence, urethritis, prostatodynia,cystitis, idiophatic bladder hypersensitivity, urinary incontinence orurinary incontinence associated with irritable bowel syndrome. In thisrespect, it may be advantageous to combine the 5HT₄-antagonisticcompounds of formula (I) with an alpha-adrenoceptor antagonist such asalfuzosin, indoramin, tamsulosin, doxazosin, terazosin, abanoquil orprazosin in order to obtain pharmaceutical compositions comprising suchan alpha-adrenoceptor antagonist, and a 5-HT₄-receptor antagonist offormula (I).

Hence, the present invention provides compounds of formula (I) for useas a medicine, and in particular the use of compounds of formula (I) forthe manufacture of a medicine for treating gastrointestinal conditionssuch as hypermotility, LBS, constipation- or diarrhea-predominant IBS,pain- and non-pain predominant LBS, bowel hypersensitivity, and thereduction of pain associated with gastrointestinal hypersensitivityand/or hyperactivity. Both prophylactic and therapeutic treatment areenvisaged.

In view of the 5HT₄-antagonistic properties of the compounds of thepresent invention, the subject compounds may also be of use in treatingor preventing 5 HT₄-related CNS disorders in a human. In particular, thecompounds of formula (I) can be used to treat a variety of CNS disordersincluding but not limited to drug substance abuse, cognitive disorderssuch as Alzheimer's disease, senile dementia; behavioral disorders suchas schizophrenia, mania, obsessive-compulsive disorder and psychoactivesubstance use disorders; mood disorders such as depression, bipolaraffective disorder, anxiety and panic disorder; disorders of control ofautonomic function such as hypertension and sleep disorders;obsessive/compulsive disorders including anorexia and bulimia, andneuropsychiatric disorders, such as Gilles de la Tourette's syndrome,and Huntington's disease.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally or by parenteral injection. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of (I) due to theirincreased water solubility over the corresponding base form, areobviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

For oral administration, the pharmaceutical compositions may take theform of solid dose forms, for example, tablets (both swallowable-onlyand chewable forms), capsules or gelcaps, prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants e.g. magnesium stearate, talc or silica);disintegrants (e.g. potato starch or sodium starch glycollate); orwetting agents (e.g. sodium lauryl sulphate). The tablets may be coatedby methods well known in the art.

Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means,optionally with pharmaceutically acceptable additives such as suspendingagents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl or propylp-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners comprise preferably at least oneintense sweetener such as saccharin, sodium or calcium saccharin,aspartame, acesulfame potassium, sodium cyclamate, alitame, adihydrochalcone sweetener, monellin, stevioside or sucralose(4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose), preferablysaccharin, sodium or calcium saccharin, and optionally a bulk sweetenersuch as sorbitol, mannitol, fructose, sucrose, maltose, isomalt,glucose, hydrogenated glucose syrup, xylitol, caramel or honey.

Intense sweeteners are conveniently employed in low concentrations. Forexample, in the case of sodium saccharin, the concentration may rangefrom 0.04% to 0.1% (w/v) based on the total volume of the finalformulation, and preferably is about 0.06% in the low-dosageformulations and about 0.08% in the high-dosage ones. The bulk sweetenercan effectively be used in larger quantities ranging from about 10% toabout 35%, preferably from about 10% to 15% (w/v).

The pharmaceutically acceptable flavours which can mask the bittertasting ingredients in the low-dosage formulations are preferably fruitflavours such as cherry, raspberry, black currant or strawberry flavour.A combination of two flavours may yield very good results. In thehigh-dosage formulations stronger flavours may be required such asCaramel Chocolate flavour, Mint Cool flavour, Fantasy flavour and thelike pharmaceutically acceptable strong flavours. Each flavour may bepresent in the final composition in a concentration ranging from 0.05%to 1% (w/v). Combinations of said strong flavours are advantageouslyused. Preferably a flavour is used that does not undergo any change orloss of taste and colour under the acidic conditions of the formulation.

The formulations of the present invention may optionally include ananti-flatulent, such as simethicone, alpha-D-galactosidase and the like.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example as a sparingly soluble salt.

The compounds of the invention may be formulated for parenteraladministration by injection, conveniently intravenous, intramuscular orsubcutaneous injection, for example by bolus injection or continuousintravenous infusion. Formulations for injection may be presented inunit dosage form e.g. in ampoules or in multidose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as isotonizing, suspending, stabilising and/ordispersing agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable vehicle, e.g. sterile pyrogen-freewater before use.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration the compounds of the invention may beused, for example, as a liquid spray, as a powder or in the form ofdrops.

In general it is contemplated that a therapeutically effective amountwould be from about 0.0001 mg/kg to about 1 mg/kg body weight,preferably from about 0.001 mg/kg to about 0.5 mg/kg body weight.

Experimental Part

In the procedures described hereinafter the following abbreviations wereused: “ACN” stands for acetonitrile; “TBF”, which stands fortetrahydrofuran; “DCM” stands for dichloromethane; “DIPE” stands fordiisopropylether, “DMF” stands for dimethylformamide, and “DMA” standsfor dimethylacetamide.

For some chemicals the chemical formula was used, e.g. NaOH for sodiumhydroxide, Na₂CO₃ for sodium carbonate, K₂CO₃ for potassium carbonate,CuO for cupper(II)oxide, NaNO₂ for sodium nitrite, CH₂Cl₂ fordichloromethane, CH₃OH for methanol, NH₃ for ammonia, HCl forhydrochloric acid, NaBF₄ for sodium tetrafluoroborate.

Chiralcel AD is a chiral stationary phase column material purchased fromDaicel Chemical Industries, LTd, in Japan.

A. Preparation of the Intermediates

EXAMPLE A.1

a) Preparation of

A mixture of methyl 2,3-dihydroxy-5-methylbenzoate (0.198 mol),1,3-dibromopropane (0.198 mol) and K₂CO₃ (0.396 mol) in 2-propanone (360ml) was stirred and refluxed for 6 hours, then cooled and the solventwas evaporated. The mixture was poured out into ice water and filtered.The filtrate was extracted with ethyl acetate. The organic layer wasseparated, dried, filtered, the solvent was evaporated and purified bycolumn chromatography over silica gel (eluent: cyclohexane/ethyl acetate80/20 to 70/30), yielding intermediate (1).

b) Preparation of

A mixture of intermediate (1) (0.1129 mol) in a mixture of a NaOHsolution 2N (370 ml) and THF (370 ml) was stirred at room temperatue for15 hours. TIW was evaporated and the mixture was acidified with HCl 12N.The precipitate was filtered, washed with water and dried, yielding 21.9g of intermediate (2) (mp. 74° C.).

EXAMPLE A.2

a) Preparation of

A mixture of 2,3-dihydroxy-4-methyl-benzoic acid methylester (1.2 mol),1,3-dibromopropane (152 ml) and K₂CO₃ (380 g) in 2-propanone (2500 ml)was stirred and refluxed for 20 hours. The reaction mixture was cooled,filtered and the filtrate was evaporated, yielding 300 g of intermediate(3).

b) Preparation of

A mixture of intermediate (3) (1.12 mol) in NaOH (2) (1800 ml) and THF(500 ml) was stirred and refluxed for 3 hours. The reaction mixture wascooled and the organic solvent was evaporated. The aqueous concentratewas acidified with HCl and the resulting precipitate was filtered off,washed with water, and dried, yielding 403 g of intermediate (4).

EXAMPLE A.3

a) Preparation of

A mixture of 5-chloro-2,3-dihydroxy-benzoic acid methyl ester (0.3 mol),1,3-dibromopropane (0.42 mol) and K₂CO₃ (0.66 mol) in 2-propanone (500ml) was stirred and refluxed for 20 hours, then filtered hot and thefiltrate was evaporated. The residue was purified by columnchromatography over silica gel (eluent: DCM). The desired fractions werecollected and the solvent was evaporated. Toluene was added andazeotroped on the rotary evaporator, yielding 69 g of methyl8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylate (intermediate5).

b) Preparation of

A mixture of intermediate (5) (0.25 mol) and KOH (1 mol) in water (650ml) was stirred and refluxed for 2 hours. The reaction mixture wascooled, acidified with HCl and the resulting precipitate was filteredoff, washed with water, and dried, yielding 48 g of8-chloro-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid(intermediate 6).

EXAMPLE A.4

a) Preparation of

A mixture of 2,3-dihydroxy-4-methoxy benzoic acid methyl ester (0.45mol), 1,3-dibromopropane (0.72 mol), K₂CO₃ (155 g) and CuO (3.6 g) inDMF (2500 ml) was stirred at 120° C. to 130° C. for 7 hours, cooled andfiltered. The solvent was evaporated. HCl (aqueous solution of 0.5 N,1000 ml)) was added. The mixture was extracted twice with DCM (750 ml).The organic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent:hexane/ethyl acetate/DCM 70/30/15). The purefractions were collected and the solvent was evaporated. The residue wascrystallized from DIPE, yielding methyl3,4-dihydro-9-methoxy-2H-1,5-benzodioxepin-6-carboxylate (intermediate7).

b) Preparation of

A NaOH solution (500 ml, 2N) was added to a solution of intermediate (7)in THF (250 ml). The mixture was stirred at room temperature overnight.The solvent was evaporated partially. The residue was extrated with DCM.The mixture was separated into its layers. The aqueous layer wasacidified with a concentrated HCl solution until pH=1 to 2. The solidwas filtered off, washed with water and dried, yielding 35.5 g of9-methoxy-3,4-dihydro-2H-1,5-benzodioxepin-6-carboxylic acid(intermediate 8).

EXAMPLE A.5

a) Preparation of

A mixture of 5-chloro-2,3-dihydroxy benzoic acid methyl ester (0.49mol), in acetic acid (2000 ml) was stirred and refluxed. A solution ofN-chlorosuccinimide (0.49 mol) in acetic acid (600 ml) was addeddropwise at reflux. The reaction mixture was stirred and refluxed for 30minutes. Extra solution of N-chlorosuccinimide (0.075 mol) in aceticacid (100 ml) was added dropwise at reflux. The reaction mixture wasstirred and refluxed for 30 minutes, then cooled and poured out intowater (500 ml). The residue was extracted with toluene (3 times). Theseparated organic layer was washed with water, dried, and evaporated.The residue was crystallized from DIPE and petroleumether, yielding 70 gof intermediate (9).

b) Preparation of

A mixture of intermediate (9) (0.3 mol), 1,3-dibromopropane (0.35 mol)and K₂CO₃ (0.7 mol) in 2-propanone (1000 ml) was stirred and refluxedfor 30 hours. The reaction mixture was cooled, diluted with water (2000ml) and extracted twice with DCM. The separated organic layer was washedwith water, dried, and the solvent was evaporated. The residue wascrystallized from DIPE and petroleumbenzine, yielding 55 g ofintermediate (10).

c) Preparation of

A mixture of intermediate (10) (0.2 mol) and KOH (1 mol) in water (1000ml) was stirred and refluxed for 90 minutes. The reaction mixture wascooled, acidified with HCl and the resulting precipitate was filteredoff, washed with water, and dried, yielding 46 g of intermediate (11).

EXAMPLE A.6

a) Preparation of

A mixture of 5-chloro-2,3-dihydroxy benzoic acid methyl ester (0.1 mol)in acetic acid (250 ml) and N-bromosuccinimide (0.11 mol) was stirredand refluxed for 4 hours. The reaction mixture was cooled and poured outinto water (500 ml). The precipitate was filtered and dried, yielding 23g of intermediate (12).

b) Preparation of

A mixture of intermediate (12) (0.7 mol), 1,3-dibromopropane (0.94 mol)and K₂CO₃ (1.55 mol) in 2-propanone (1300 ml) was stirred and refluxedfor 20 hours. The reaction mixture was cooled, filtered and the solventwas evaporated. The residue was solidified in petroleumether, filteredand dried, yielding 240 g of intermediate (13).

c) Preparation of

A mixture of intermediate (13) (0.053 mol) and KOH (0.2 mol) in water(160 ml) was stirred and refluxed for 90 minutes. The reaction mixturewas cooled and the aqueous layer was extracted with DCM. The aqueouslayer was acidified with HCl and the resulting precipitate was filteredoff, washed with water, and dried, yielding 13 g of intermediate (14).

EXAMPLE A.7

a) Preparation of

A mixture of 5-nitro-2,3-dihydroxybenzoic acid methylester (0.3 mol),K₂CO₃ (0.66 mol), 1,3-dibromopropane (0.42 mol) andtetra-n-butylammonium bromide (4.5 g) in 2-propanone (900 ml) and DMA(600 ml) was stirred and refluxed for 30 hours. The reaction mixture wasstirred for two days at room temperature and then filtered. The solventwas evaporated and the residue was partitioned between water and DCM.The separated organic layer was dried, filtered and concentrated. Theresidue was suspended in DIPE, filtered, dried and purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2), yielding33.5 g of intermediate (15).

b) Preparation of

A mixture of intermediate (15) (0.11 mol) in TBF (250 ml) washydrogenated with palladium-on-carbon 10% (3 g) as a catalyst in thepresence of a thiophene-solution (1 ml). After uptake of hydrogen (3equivalents), the catalyst was filtered off over dicalite and thefiltrate was concentrated, yielding 24.7 g of intermediate (16).

c) Preparation of

Intermediate (16) (0.0448 mol) was added portionwise at 5° C. to amixture of concentrated HCl (10 ml) in water (10 ml). The mixture wasbrought to 0° C. A solution of NaNO₂ (0.048 mol) in water (10 ml) wasadded dropwise at 0° C. The mixture was stirred at a temperature between0° C. and 5° C. for 1 hour, then filtered. The filtrate was cooled to 0°C., then added to a solution of NaBF₄ (0.076 mol) in water (20 ml). Themixture was stirred at 0° C. for 30 minutes. The precipitate wasfiltered, washed with a minimum of water, then with diethyl ether/water(50/50), then with diethyl ether and dried at room temperature undervacuo, yielding 12.10 g of intermediate (17).

d) Preparation of

A mixture of intermediate (17) (0.0387 mol) and sodium fluoride (0.1549mol) in toluene (120 ml) was stirred and refluxed overnight, thenbrought to room temperature. The precipitate was filtered. The filtratewas washed with toluene and evaporated till dryness. The residue wastaken up in DCM. The solvent was evaporated till dryness. The residuewas purified by column chromatography over silica gel (eluent: DCM),yielding 2.8 g of intermediate (18).

e) Preparation of

A mixture of intermediate (18) (0.0124 mol) in a NaOH solution (2N, 25ml) and THF (25 ml) was stirred at room temperature overnight. TBF wasevaporated and ethyl acetate was added. The mixture was extracted withethyl acetate, then acidified with HCl till pH 2 was obtained. Theprecipitate was filtered, washed with water, then with diethyl ether anddried, yielding 2.16 g of intermediate (19).

EXAMPLE A.8

Preparation of

A mixture of 1,1-dimethylethyl(trans)-3-hydroxy4-[[(phenylmethyl)amino]methyl]-1-piperidinecarboxylate[described in WO-00/37461 as intermediate (1-d)] (0.023 mol) in methanol(100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as acatalyst. After uptake of hydrogen (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated. The residue was solidifiedin DIPE+ACN, filtered off and dried, yielding 4 g of 1,1-dimethylethyl(trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate (intermediate20, mp. 178° C.).

EXAMPLE A.9

a) Preparation of

1,1-Dimethylethyl(trans)-3-hydroxy-4-[[(phenylmethyl)amino]methyl]-1-piperidinecarboxylate[described in WO-00/37461 as intermediate (1-d)] (2.73 mol) wasseparated and purified by chiral column chromatography over Chiralcel AD(eluent:hexane/ethanol 80/20). The desired fractions were collected andthe solvent was evaporated. Toluene was added and azeotroped on therotary evaporator, yielding 377 g of 1,1-dimethylethyl(3S-trans)-3-hydroxy-4-[[(phenylmethyl)amino]methyl]-1-piperidinecarboxylate(intermediate 21).

b) Preparation of

A mixture of intermediate (21) (0.028 mol) in methanol (100 ml) washydrogenated with palladium-on-carbon (10%, 2 g) as a catalyst. Afteruptake of hydrogen (1 equivalent) the catalyst was filtered off and thefiltrate was evaporated, yielding 4.7 g of 1,1-dimethylethyl(3S-trans)-4-(aminomethyl)-3-hydroxy-1-piperidinecarboxylate(intermediate (22); [α]_(D) ²⁰=+4.37° (c=24.03 mg/5 ml in CH₃OH)).

EXAMPLE A.10

a) Preparation of

Reaction under nitrogen atmosphere. Sodiumhydride (0.3 mol) was added toa solution of 1,1-dimethylethyltrans-3-hydroxy-4-[[[(methylphenyl)sulfonyl]oxy]methyl]-1-piperidinecarboxylate[described in WO-00/37461 as intermediate (1-c)] (0.27 mol) in THP (1300ml). The mixture was stirred for 30 minutes. Methyliodide (0.54 mol) wasadded and the resulting reaction mixture was stirred for 90 minutes. Asmall amount of water was added. The solvent was evaporated and theresidue was partitioned between water and DCM. The organic layer wasseparated, dried, filtered and the solvent was evaporated, yielding1,1-dimethylethyltrans-4-[[[(4-methylphenyl)sulfonyl]oxy]-methyl]-3-methoxy-1-piperidinecarboxylate(intermediate 23).

b) Preparation of

A mixture of intermediate (23) (0.065 mol) in THF (250 ml) was treatedwith liquid NH₃ in an autoclave at 125° C. during 16 hours. The reactionmixture was filtered and the filtrate was evaporated. The residue waspartitioned between a 5% aqueous NaOH solution and DCM. The organiclayer was separated, dried, filtered and the solvent was evaporated,yielding 16 g of 1,1-dimethylethyl(trans)₄-(aminomethyl)-3-methoxy-1-piperidinecarboxylate (intermediate(24).

EXAMPLE A.11

a) Preparation of

A mixture of intermediate (2) (0.336 mol) and triethylamine (0.4 mol) inDCM (1000 ml) was stirred at 5° C., then ethyl chloroformate (0.35 mol)was added dropwise and the reaction mixture was stirred for 30 minutes.To this mixture, a solution of intermediate (22) (83 g) in DCM (1000 ml)was added at 5° C., then the reaction mixture was allowed to reach roomtemperature and was washed with water. The organic layer was separated,dried, filtered and the solvent was evaporated, yielding 150 g ofintermediate (25).

b) Preparation of

A mixture of intermediate (25) (0.336 mol) in 2-propanol saturated withHCl (160 ml) and 2-propanol (1400 ml) was stirred and refluxed for 1hour. The solvent was evaporated and the residue was taken up in amixture of DCM and a small amount of methanol. The mixture was washedwith an aqueous ammonia solution and the organic layer was separated,dried, filtered. The solvent was evaporated, yielding 71 g ofintermediate (26).

TABLE I-1 intermediates (27) to (36) were prepared according to the sameprocedure of Example A.11 Intermediate Structure Physical data 27

trans; 28

3S-trans: mp. 215° C.;[α]_(D) ²⁰ = −14.03° (c = 23.88 mg/5 mlinmethanol) 29

3S-trans: mp. 114° C.;[α]_(D) ²⁰ = −14.34° (c = 24.41 mg/5 mlinmethanol) 30

trans; .HCl (1:1); mp. 173° C. 31

trans; .HCI (1:1); mp. 206° C. 32

trans; 33

trans; 34

trans; .HCl (1:1); mp. 220° C. 35

trans; 36

trans; ; mp. 145° C.B. Preparation of the Final Compounds

EXAMPLE B.1

a) Preparation of

A mixture of intermediate (27) (0.0156 mol), ethyl2-(3-chloropropoxy)-benzoic acid ester (0.0187 mol) and K₂CO₃ (0.037mol) in acetonitril (50 ml) was refluxed overnight, poured out into icewater and extracted with ethyl acetate. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH94/6/0.5).

The pure fractions were collected and the solvent evaporated, yieldingintermediate (37) (mp. 116° C.).

b) Preparation of

Lithium hydroxide monohydrate (0.0113 mol) was added at room temperatureto a mixture of intermediate (38) (0.0056 mol) in TBf (30 ml) and water(30 ml). The mixture was stirred at room temperature overnight. THF wasevaporated. The mixture was acidified with HCl (3N) and extracted withDCM. The organic layer was separated, dried, filtered, and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 80/20/1 then eluent:CH₂Cl₂/CH₃OH/NH₄OH 70/30/2), yielding compound (1) (mp. 114° C.).

Table F-1 lists the compounds that were prepared according to theprocedure of Example B.1 by reacting one of the intermediates (26) to(36) with one of the following compounds methyl4-(4-chlorobutoxy)-benzoic acid ester, methyl 4-(4-chloroethoxy)-benzoicacid ester, ethyl 3(3-chloropropoxy)-benzoic acid ester, ethyl4(3-chloropropoxy)-benzoic acid ester, or ethyl2-(3-chloropropoxy)-benzoic acid ester.

TABLE F-1

Co. No. R^(a) n R³ R⁴ R⁵ Physical data 1 2-HOOC 3 H CH₃ H trans; mp.114° C. 2 4-HOOC 4 H CH₃ H 3S-trans; mp. 188° C.; [α]_(D) ²⁰ = −11.00°(c = 23.63 mg/5 ml in methanol) 3 4-HOOC 4 CH₃ H H 3S-trans; mp. 170°C.; [α]_(D) ²⁰ = −11.71° (c = 23.06 mg/5 ml in methanol) 4 4-HOOC 2 H ClH 3S-trans; mp. 220-225° C. 5 4-HOOC 4 H Cl H 3S-trans; mp. 190° C.;[α]_(D) ²⁰ = −10.29° (c = 26.23 mg/5 ml in methanol) 6 4-HOOC 2 H CH₃ H3S-trans; mp. 175° C.; [α]_(D) ²⁰ = −9.21° (c = 24.96 mg/5 ml inmethanol) 7 2-HOOC 3 H Cl H trans; mp. 148° C. 8 4-HOOC 2 CH₃ H H3S-trans; .HCI (1:1) .H₂O (1:1); mp. >120° C.; [α]_(D) ²⁰ = −13.52° (c =24.04 mg/5 ml in methanol) 9 4-HOOC 3 H Cl H trans; mp. 122° C. 103-HOOC 3 H Cl H trans 11 3-HOOC 3 CH₃ H H 3S-trans; mp. 120° C.; [α]_(D)²⁰ = −11.05° (c = 9.23 mg/2 ml in methanol) 12 3-HOOC 3 H CH₃ H trans;mp. 122° C. 13 4-HOOC 3 H CH₃ H trans; mp. 118° C. 14 4-HOOC 3 CH₃ H H3S-trans; mp. 155° C.; [α]_(D) ²⁰ = −8.03° (c = 12.20 mg/2 ml inmethanol) 15 2-HOOC 3 CH₃ H H 3S-trans; .H₂O (1:1); mp. 156° C.; [α]_(D)²⁰ = −13.34° (c = 11.54 mg/2 ml in methanol) 16 4-HOOC 3 Cl Cl H trans;.HCl (1:1); mp. 256° C. 17 4-HOOC 3 Br Cl H trans; .HCl (1:1) .H₂O(1:2); mp. 268° C. 18 4-HOOC 3 Br Cl CH₃ trans; .HCl (1:1) .H₂O (2:3);mp. 136° C. 19 4-HOOC 3 H F CH₃ trans; mp. 187.7-198.6° C. 20 4-HOOC 3Cl Cl CH₃ trans; mp. 200° C. 21 4-HOOC 3 CH₃O H CH₃ trans; mp179.4-189.2° C. 22 4-HOOC 3 H CH₃ CH₃ trans

PHARMACOLOGICAL EXAMPLES EXAMPLE C.1 5HT₄ Antagonism

h5-HT_(4b)-HEK 293 clone 9 cells were cultured in 150 mm Petri dishesand washed twice with cold PBS. The cells were then scraped from theplates and suspended in 50 mM Tris-HCl buffer, pH 7.4 and harvested bycentrifugation at 23,500 rpm for 10 minutes. The pellet was resuspendedin 5 mM Tris-HCl, pH 7.4 and homogenized with an Ultra Turraxhomogenizer. The membranes were collected by centrifugation at 30,000rpm for 20 min, resuspended in 50 mM Tris-HCl pH 7.4 and stored at −80°C. For the experiment, assay mixtures (0.5 ml) contained 50 μl of thetritiated ligand (5-HT₄ antagonist [³H]GR113808 0.1 nM) and 0.4 mlmembrane preparation (15 μg protein/ml). 50 μl of 10% DMSO was added fortotal binding. 50 μl of 1 μM of(+)-trans-(1-butyl-3-hydroxy-4-piperidinyl)methyl8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (aproprietary 5HT₄ agonist of Janssen Pharmaceutica) was added fordetermination of non-specific binding.

The [³H]GR113808 assay buffer was 50 mM HEPES-NaOH, pH 7.4. The mixtureswere incubated for 30 min at 25° C. The incubation was terminated byfiltration over a Unifilter 96 GF/B presoaked in 0.1% polyethylenimine,followed by six washing steps with 50 mM HEPES-NaOH, pH 7.4.

Ligand concentration binding isotherms (rectangular hyperbola) werecalculated by nonlinear regression analysis and the pIC₅₀ data for alltested compounds are listed below in Table C. 1.

TABLE C.1 5HT₄ antagonistic data Co. No. pIC₅₀ 1 6.92 2 8.02 3 8.31 47.84 5 8.29 6 7.2 7 7.1 8 7.37 9 7.95 10 7.5 11 8.07 12 7.63 13 7.68 148.06 15 7.02 16 8.12 17 8.25 18 8.15 19 7.74 20 8.11 21 7.18 22 7.87

EXAMPLE C.2 Metabolic Stability

Sub-cellular tissue preparations were made according to Gorrod et al.(Xenobiotica 5: 453-462, 1975) by centrifugal separation aftermechanical homogenization of tissue. Liver tissue was rinsed in ice-cold0.1 M Tris-HCl (pH 7.4) buffer to wash excess blood. Tissue was thenblotted dry, weighed and chopped coarsely using surgical scissors. Thetissue pieces were homogenized in 3 volumes of ice-cold 0.1 M phosphatebuffer (pH 7.4).

Tissue homogenates were centrifuged at 9000×g for 20 minutes at 4° C.The resulting supernatant was stored at −80° C. and is designated ‘S9’.

The S9 fraction can be further centrifuged at 100.000×g for 60 minutes(4° C.). The resulting supernatant was carefully aspirated, aliquotedand designated ‘cytosol’. The pellet was re-suspended in 0.1 M phosphatebuffer (pH 7.4) in a final volume of 1 ml per 0.5 g original tissueweight and designated ‘microsomes’.

All sub-cellular fractions were aliquoted, immediately frozen in liquidnitrogen and stored at −80° C. until use.

For the samples to be tested, the incubation mixture contained PBS(0.1M), compound (5 μM), microsomes (1 mg/ml) and a NADPH-generatingsystem (0.8 mM glucose-6-phosphate, 0.8 mM magnesium chloride and 0.8Units of glucose-6-phosphate dehydrogenase). Control samples containedthe same material but the microsomes were replaced by heat inactivated(10 minutes at 95 degrees Celsius) microsomes. Recovery of the compoundsin the control samples was always 100%.

The mixtures were preincubated for 5 minutes at 37 degrees Celsius. Thereaction was started at time point zero (t=0) by addition of 0.8 mM NADPand the samples were incubated for 60 minutes (t=60). The reaction wasterminated by the addition of 2 volumes of DMSO. Then the samples werecentrifuged for 10 minutes at 900×g and the supernatants were stored atroom temperature for no longer as 24 hours before analysis. Allincubations were performed in duplo. Analysis of the supernatants wasperformed with LC-MS analysis. Elution of the samples was performed on aXterra MS C18 (50×4.6 mm, 5 μm, Waters, US). An Alliance 2790 (Supplier:Waters, US) HPLC system was used. Elution was with buffer A (25 mMammoniumacetate (pH 5.2) in H₂O/acetonitrile (95/5)), solvent B beingacetonitrile and solvent C methanol at a flow rate of 2.4 ml/min. Thegradient employed was increasing the organic phase concentration from 0%over 50% B and 50% C in 5 min up to 100% B in 1 minute in a linearfashion and organic phase concentration was kept stationary for anadditional 1.5 minutes. Total injection volume of the samples was 25 μl.

A Quatro triple quadrupole mass spectrometer fitted with and ESP sourcewas used as detector. The source and the desolvation temperature wereset at 120 and 350° C. respectively and nitrogen was used as nebuliserand drying gas. Data were acquired in positive scan mode (single ionreaction). Cone voltage was set at 10 V and the dwell time was 1 second.

Metabolic stability was expressed as % metabolism of the compound after60 minutes (equation given as example) of incubation in the presence ofactive microsomes (E(act))

$\left( {{\%\mspace{14mu}{metabolism}} = {{100\%} - {\left( {\left( \frac{{{Total}\mspace{14mu}{Ion}\mspace{14mu}{{Current}({TIC})}{of}\mspace{14mu}{E({act})}{at}\mspace{14mu} t} = 60}{{{TIC}\mspace{14mu}{of}\mspace{14mu}{E({act})}{at}\mspace{14mu} t} = 0} \right) \times 100} \right).}}} \right.$

TABLE C.2 % metabolised compound after 60 minutes Co. No. % metabolized2 6 3 16 5 15 7 14 9 7.5 10 13.5 11 1 12 0 14 0 15 6.5 16 3 17 6 18 2022 6

1. A compound of formula (I)

a stereochemically isomeric form thereof an N-oxide form thereof or apharmaceutically acceptable acid or base addition salt thereof, wherein—R¹—R²— is a bivalent radical of formula—O—CH₂—O—  (a-1),—O—CH₂—CH₂—  (a-2),—O—CH₂—CH₂—O—  (a-3),—O—CH₂—CH₂—CH₂—  (a-4),—O—CH₂—CH₂—CH₂—O—  (a-5),—O—CH₂—CH₂—CH₂—CH₂—  (a-6),—O—CH₂—CH₂—CH₂—CH₂—O—  (a-7),—O—CH₂—CH₂—CH₂—CH₂—CH₂—  (a-8), wherein in said bivalent radicalsoptionally one or two hydrogen atoms on the same or a different carbonatom may be replaced by C₁₋₆alkyl or hydroxy, R³ is hydrogen, halo,C₁₋₆alkyl or C₁₋₆alkyloxy; R⁴ is hydrogen, halo, C₁₋₆alkyl; C₁₋₆alkylsubstituted with cyano, or C₁₋₆alkyloxy; C₁₋₆alkyloxy; cyano; amino ormono or di(C₁₋₆alkyl)amino; R⁵ is hydrogen or C₁₋₆alkyl, and the —OR⁵radical is situated at the 3- or 4-position of the piperidine moiety; Lis a radical of formula-Alk-R⁶  (b-1),-Alk-X—R⁷  (b-2),-Alk-Y—C(═O)—R⁹  (b-3), wherein each Alk is C₁₋₂alkanediyl; and R⁶ isaryl; R⁷ is aryl; X is O, S, SO₂ or NR⁸; said R⁸ being hydrogen orC₁₋₆alkyl; R⁹ is aryl; Y is a direct bond, O, S, or NR¹⁰ wherein R¹⁰ ishydrogen or C₁₋₆alkyl; and aryl represents phenyl substituted with 1, 2or 3 hydroxycarbonyl.
 2. The compound as claimed in claim 1 wherein the—OR⁵ radical is situated at the 3-position of the piperidine moietyhaving the trans configuration.
 3. The compound as claimed in claim 2wherein the absolute configuration of said piperidine moiety is (3S,4S).
 4. The compound as claimed in claim 1 wherein L is a radical offormula (b-2) wherein Alk is C₁₋₄alkanediyl, and R⁷ is aryl wherein arylis phenyl substituted with hydroxycarbonyl.
 5. The compound as claimedin claim 4 wherein Alk is 1,3-propanediyl or 1,4-butanediyl.
 6. Thecompound as claimed in claim 5 wherein R⁷ is aryl wherein aryl is phenylsubstituted with hydroxycarbonyl situated at the 3- or 4-position of thephenyl moiety.
 7. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically active amountof a compound according to claim
 1. 8. A method for treatinggastorintestinal hypermotility, irritable bowel syndrome, constipationor diarrhea predominant IDS, pain and non-pain predominant IBS and bowelhypersensitivity comprising administering to a patient in need thereofan effective amount of a compound according to claim
 1. 9. A process forpreparing a compound of formula (1) wherein a) an intermediate offormula (II) is reacted with an carboxylic acid derivative of formula(III) or a reactive functional derivative thereof;

b) an intermediate of formula (IV) is N-alkylated with an intermediateof formula (V), in a reaction-inert solvent and, optionally in thepresence of a suitable base;

wherein in the above reaction schemes the radicals —R¹—R²—, R³, R⁴, R⁵,and L are as defined in claim 1 and W is an appropriate leaving group;c) or, compounds of formula (I) are converted into each other followingart-known transformation reactions; or if desired; a compound of formula(I) is converted into a pharmaceutically acceptable acid addition salt,or conversely, an acid addition salt of a compound of formula (I) isconverted into a free base form with alkali; and, if desired, preparingstereochemically isomeric forms thereof.